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| | <StructureSection load='6zvl' size='340' side='right'caption='[[6zvl]], [[Resolution|resolution]] 1.30Å' scene=''> | | <StructureSection load='6zvl' size='340' side='right'caption='[[6zvl]], [[Resolution|resolution]] 1.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6zvl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZVL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZVL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zvl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZVL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZVL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QR2:5-[4-chloranyl-3-(trifluoromethyl)phenyl]-3~{H}-1,3,4-oxadiazol-2-one'>QR2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6zuv|6zuv]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QR2:5-[4-chloranyl-3-(trifluoromethyl)phenyl]-3~{H}-1,3,4-oxadiazol-2-one'>QR2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOTUM, OK/SW-CL.30 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zvl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zvl OCA], [https://pdbe.org/6zvl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zvl RCSB], [https://www.ebi.ac.uk/pdbsum/6zvl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zvl ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zvl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zvl OCA], [http://pdbe.org/6zvl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zvl RCSB], [http://www.ebi.ac.uk/pdbsum/6zvl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zvl ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN]] May deacetylate GlcNAc residues on cell surface glycans. | + | [https://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN] May deacetylate GlcNAc residues on cell surface glycans. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6zvl" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6zvl" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ruza, R]] | + | [[Category: Ruza R]] |
| - | [[Category: Zhao, Y]] | + | [[Category: Zhao Y]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Notum]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Wnt]]
| + | |
| Structural highlights
6zvl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.3Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
NOTUM_HUMAN May deacetylate GlcNAc residues on cell surface glycans.
Publication Abstract from PubMed
Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.
5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit.,Mahy W, Willis NJ, Zhao Y, Woodward HL, Svensson F, Sipthorp J, Vecchia L, Ruza RR, Hillier J, Kjaer S, Frew S, Monaghan A, Bictash M, Salinas PC, Whiting P, Vincent JP, Jones EY, Fish PV J Med Chem. 2020 Oct 30. doi: 10.1021/acs.jmedchem.0c01391. PMID:33124429[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mahy W, Willis NJ, Zhao Y, Woodward HL, Svensson F, Sipthorp J, Vecchia L, Ruza RR, Hillier J, Kjaer S, Frew S, Monaghan A, Bictash M, Salinas PC, Whiting P, Vincent JP, Jones EY, Fish PV. 5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit. J Med Chem. 2020 Oct 30. doi: 10.1021/acs.jmedchem.0c01391. PMID:33124429 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01391
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